The objective of this program is to improve understanding of genetic susceptibility to lung cancer. Tobacco smoking is recognized as the primary cause of lung cancer. DNA and chromosomal damage induced by mutagenic carcinogens in tobacco smoke is thought to be a key feature in the initiation of lung carcinogenesis, although the specific carcinogens involved have not been identified. Epidemiologic studies have shown the association of genetic polymorphisms in drug and carcinogen metabolism with lung cancer, indicating that cancer risk may be a result of genetic-environmental interactions. Genetic polymorphisms in debrisoquine metabolism, aryl hydrocarbon hydroxylase inducibility, and glutathione-S-transferase mu have been linked to lung cancer. The mechanisms responsible for the association of these genetic traits with lung cancer are unknown. We propose that increased lung cancer risk associated with genetic variations in drug and carcinogen metabolism are the result of increased susceptibility to the induction of DNA damage in the target tissue. To test this hypothesis a case-control study will be performed. We will determine if the genetic traits which have been reported to confer susceptibility to smoking-related lung cancer act multiplicatively. We will investigate the association of biologic markers of carcinogen exposure and response, studied in both target and surrogate tissues, with these defined genetic and environmental parameters of risk. This Program design affords the opportunity for intensive study of the mechanisms mediating susceptibility of humans to smoking-induced lung cancer.